Drug Metabolizing Enzyme and Transporter Function in Chronic Kidney Disease

慢性肾病的药物代谢酶和转运蛋白功能

• 批准号: 8759210
• 负责人: MELANIE S JOY
• 金额: $ 47.06万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8759210
• 关键词: Address; Adverse effects; Affect; Animals; Autoimmune Diseases; Bupropion; CYP2B6 gene; CYP3A4 gene; Caring; Catalysis; Cholecalciferol; Chronic Kidney Failure; Clinical; Communicable Diseases; Confusion; Cytochrome P450; Data; Dihydroxycholecalciferols; Disease; Dose; Drug Interactions; Drug Kinetics; Drug Transport; Enzymes; Exposure to; Future; Gene Expression Regulation; Genes; Genomics; Goals; Guidelines; Health; Health Benefit; Hepatocyte; Homeostasis; Human; In Vitro; Individual; Investigation; Kidney; Kidney Diseases; Liver; Maintenance; Measures; Mediating; Medication Management; Metabolism; Midazolam; Monitor; Morbidity - disease rate; Musculoskeletal; Organ; Outcome; POU2F2 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Principal Investigator; Public Health; Publishing; Regimen; Regulation; Research; Risk; Role; Route; Serum; Severities; Simulate; Staging; Toxic effect; Transport Process; Uremia; Variant; Vitamin D; Vitamin D Analog; Vitamin D Deficiency; Xenobiotic Metabolism; Xenobiotics; base; bone; cancer prevention; cardiovascular risk factor; clinical risk; cohort; drug clearance; drug metabolism; fexofenadine; healthy volunteer; improved; in vivo; kidney cell; mortality; olmesartan; pharmacokinetic model; public health relevance; translational study

DESCRIPTION (provided by applicant): This proposal focuses on the role of vitamin D as a modulator of xenobiotic clearance in patients with chronic kidney disease (CKD). Vitamin D can influence the regulation of genes responsible for metabolism and transport processes that mediate xenobiotic clearance. This is highly relevant since vitamin D treatment is common, as deficiency (total 25(OH)D level <30 ng/mL) is observed in up to 90% of CKD cohorts. Previous published research by the Principal Investigators and others has shown that renal and nonrenal xenobiotic clearance pathways mediated by cytochrome P450 (CYP) enzymes and transporters is altered in CKD. Given the 24 M US citizens with CKD are prescribed an average of 10-12 different medications daily, the clinical realities of altered xenobiotic clearance in CKD (drug interactions, side effects, altered efficacy, and confusion for clinicians prescribing and/or monitoring treatments) are not trivial. Importantly, increasing evidence indicates that vitamin D deficiency is a significant non-traditional cardiovascular risk factor, and vitamin D is important or bone and musculoskeletal health, kidney protection, cancer prevention, and decreased severity or risk of autoimmune and infectious diseases. In this proposal, we developed a translational study employing in vivo and in vitro studies to investigate how vitamin D alters the activity of drug metabolism and transport pathways in CKD. We propose to characterize the in vivo activity of xenobiotic metabolism and transport pathways in CKD patients and healthy controls under the opposing influences of vitamin D deficiency and repletion. Moreover, physiologically-based pharmacokinetic models will explore mechanisms for vitamin D and uremia on variations in drug metabolism and transport using data derived from the planned in vivo and in vitro studies. Our central hypothesis is that vitamin D status independently affects metabolism and transport function in CKD patients. An over-arching goal of this proposal is to make drug therapies safer and more effective to reduce the significant morbidity and mortality in patients with CKD. Three independent Specific Aims comprised of in vivo and in vitro studies were formulated to address the key hypotheses: 1) The in vivo function of individual pathways of xenobiotic metabolism and transport are affected by vitamin D status and by CKD, 2) CKD alters the activity of individual CYPs responsible for vitamin D metabolism, leading to modified pharmacokinetics of cholecalciferol, and 3) Vitamin D treatment and simulated CKD differentially alter the expression and function of drug metabolizing enzymes and transporters in kidney and liver cells. These studies will be central to determine where more scrutiny is warranted in evaluating clinical risks for drug interactions, altered efficacy and toxicity of therapies, and for guidance on appropriate vitamin D deficiency and maintenance regimens. Long term benefits of this research are improvements in medication management, drug dosing guidelines, and corresponding outcomes in targeted organs and/or diseases for vitamin D treated patients. The proposed research would have high impact through the public health benefit of improving care provided to CKD patients, serving as a basis for future study of alterations in drug metabolism and transport, and provision of much needed information on vitamin D metabolism and pharmacokinetics in CKD.

描述（由申请人提供）：该提案重点介绍维生素D作为异生元素清除率在慢性肾脏病（CKD）患者中的作用。维生素D可以影响负责代谢的基因和介导异生物清除率的转运过程。这是非常相关的，因为维生素D治疗很常见，因为在多达90％的CKD队列中观察到缺乏症（总计25（OH）D水平<30 ng/ml）。首席研究者和其他人的先前发表的研究表明，CKD中的细胞色素P450（CYP）酶和转运蛋白介导的肾脏和肾异生物清除途径在CKD中发生了变化。鉴于CKD的24 M美国公民每天平均处方10-12种不同的药物，因此CKD中异种生物清除率改变的临床现实（药物相互作用，副作用，疗效改变以及对临床医生处方和/或监测治疗的混乱）并非微不足道。重要的是，越来越多的证据表明，维生素D缺乏症是一种重要的非传统心血管危险因素，维生素D是重要的，骨骼和肌肉骨骼健康，肾脏保护，预防癌症，癌症预防以及降低了自身免疫性和感染性疾病的严重程度或风险。在这项建议中，我们开发了一项翻译研究，该研究采用体内和体外研究来研究维生素D如何改变CKD中药物代谢和运输途径的活性。我们建议表征CKD患者中异生物代谢和转运途径的体内活性以及维生素D缺乏症和补充的相对影响下的健康对照。此外，基于生理的药代动力学模型将探索使用源自计划的体内和体外研究的数据，探索维生素D和尿emia在药物代谢和运输方面的变化机制。我们的中心假设是，维生素D状态独立影响CKD患者的新陈代谢和运输功能。该提案的一个超大目标是使药物疗法更安全，更有效，以降低CKD患者的显着发病率和死亡率。 Three independent Specific Aims comprised of in vivo and in vitro studies were formulated to address the key hypotheses: 1) The in vivo function of individual pathways of xenobiotic metabolism and transport are affected by vitamin D status and by CKD, 2) CKD alters the activity of individual CYPs responsible for vitamin D metabolism, leading to modified pharmacokinetics of cholecalciferol, and 3)维生素D处理和模拟CKD差异改变了肾脏和肝细胞中药物代谢酶和转运蛋白的表达和功能。这些研究将是确定在评估药物相互作用，疗效改变和毒性的临床风险以及对适当的维生素D缺乏症和维持方案的指导方面的临床风险时需要进行更多审查的核心。这项研究的长期益处是改善药物管理，药物剂量指南以及对维生素D治疗患者的靶向器官和/或疾病的相应结果。拟议的研究将通过改善为CKD患者提供的护理的公共卫生益处产生很大的影响，这是对药物代谢和运输变化的未来研究的基础，并提供有关CKD中维生素D代谢和药代动力学的急需信息。